Highly efficient synthesis of the tricyclic core of taxol by cascade metathesis

Article abstract of DOI:10.1021/ol501304j

An efficient enantioselective synthesis of the ABC tricyclic core of the anticancer drug Taxol is reported. The key step of this synthesis is a cascade metathesis reaction, which leads in one operation to the required tricycle if appropriate fine-tuning o

Full text of DOI:10.1021/ol501304j

Letter
pubs.acs.org/OrgLett
Highly Efficient Synthesis of the Tricyclic Core of Taxol by Cascade
Metathesis
Aurelien Letort,† Remi Aouzal,‡,§ Cong Ma,‡,∥ De-Liang Long,† and Joelle Prunet*,†
́
́
̈
†WestCHEM, School of Chemistry, University of Glasgow, Joseph Black Building, University Avenue, Glasgow G12 8QQ, U.K.
‡Laboratoire de Synthes
e Organique, CNRS UMR 7652, Ecole Polytechnique, DCSO, 91128 Palaiseau, France
̀
S
* Supporting Information
ABSTRACT: An efficient enantioselective synthesis of the
ABC tricyclic core of the anticancer drug Taxol is reported.
The key step of this synthesis is a cascade metathesis reaction,
which leads in one operation to the required tricycle if
appropriate fine-tuning of the dienyne precursor is performed.
axol (Scheme 1) and its derivatives are the largest selling
toward Taxol,15 we aimed for a compound described by Holton
et al.3b (Scheme 1). This intermediate could be synthesized
from compound 1 (R = OBOM), using Danishefsky’s route to
convert the C3−C4 alkene into the ketone5 and Granja’s
method to install the 11-ene-10,13 diol from the C10−C13
diene.16 Herein, we report a synthetic strategy to the ABC
tricyclic core of Taxol 1, featuring a challenging cascade ene-
yne-ene ring-closing metathesis (RCDEYM) reaction17 that
allows a highly efficient access to this compound. Although
such a cascade metathesis has already been employed by
Granja’s12 and our group18 for the synthesis of model ABC
tricycle of taxoids, in each case the relative stereochemistry of
these analogues at C1, C2, and C8 was different from the one
found in Taxol. Moreover, the gem dimethyl group bridging the
A and B rings, whose steric hindrance presents a major
difficulty in the synthesis of Taxol, was either not present12 or
not positioned at the proper place.18
T
anticancer drugs of all time,1 and they are employed to
Scheme 1. Retrosynthesis of Taxol
We elected to validate our approach on the 7-deoxy ABC
ring system 1 (R = H) (Scheme 1). Enyne metathesis of
compound 3 between the alkene at C10 and the alkyne at C11
would produce the intermediate carbene 2, which would lead to
compound 1 after subsequent diene RCM. In order to direct
the metathesis cascade so it will start with the olefin at C10, we
chose to have a di- or trisubstituted olefin at C13 (R1 = Me, R2
= H, Me), which would react more slowly with the metathesis
catalysts. Dienyne 3 would be constructed by a Shapiro
coupling between aldehyde 4 and hydrazone 5.
The synthesis of the required aldehydes started from the
known acid 619 (Scheme 2), which is easily prepared from ethyl
isobutyrate in two steps (81% overall yield). Isomerization of
the terminal alkyne into the more stable internal alkyne was
performed by heating 6 at 75 °C in DMSO in the presence of
potassium tert-butoxide20 in 93% yield, and the acid 7 was then
treat a wide range of malignancies.2 There have been six total
syntheses of Taxol by the groups of Holton,3 Nicolaou,4
Danishefsky,5 Wender,6 Mukaiyama,7 and Kuwajima,8 as well as
one formal synthesis by Takahashi et al.9 Other elegant
approaches leading to the ABC tricyclic core of taxane
derivatives include work by the groups of Swindell,10
Pattenden,11 Granja,12 Winkler,13 and Baran.14 In our approach
Received: May 7, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ol501304j | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
be prepared using an enantioselective cyanation reaction,18 but
we chose to pursue the synthesis of the metathesis precursors
with the racemic aldehyde to study the influence of the
stereochemistry of the precursors on the RCDEYM reaction
outcome.
Scheme 2. Synthesis of Aldehydes ( )-9 and ( )-12 for
Shapiro Coupling
Hydrazone 1315h (Scheme 3) was reacted with aldehyde
( )-9 using the conditions we developed previously.15h As had
been observed for model aldehydes,15d this reaction was highly
diastereoselective, giving compounds 14a and 14b after
hydrolysis of the trimethylsilyl ether in excellent combined
yield. These diols 14a and 14b were then submitted separately
to the protection of the C1−C2 diol as the cyclic carbonate,
triphenylmethyl ether hydrolysis, and dehydration of the
resulting primary alcohol using the Grieco protocol22 to furnish
the metathesis precursors 15a and 15b in 72% and 57% overall
yield for the four steps, respectively. When the aldehyde
( )-12 was engaged in the Shapiro coupling, the trans diols
16a and 16b were obtained in 76% combined yield (Scheme
3). These diols were separately converted into the correspond-
ing carbonates 17a and 17b in 76% and 77% overall yield,
respectively, using the same protocols as that for the synthesis
of 15a and 15b.
The key metathesis step was then studied. Carbonates 15a
and 15b both failed to produce tricyclic products, but led to the
bicycles 18a and 18b resulting from a diene metathesis reaction
between the olefins at C10 and C13 (Scheme 4). These
carbonates were converted to the corresponding benzoates 19a
and 19b by treatment with phenyllithium, as we have shown
that the nature of the diol protecting group plays a crucial role
in the outcome of metathesis reactions leading to BC ring
systems of taxol.15h These benzoates 19a,b also underwent
diene metathesis, and the bicyclic benzoates 20a and 20b were
obtained in very good yields. E and Z isomers of 15a,b and
19a,b exhibited the same behavior. We concluded that the
steric hindrance around the alkyne was disfavoring the initial
enyne metathesis for all these substrates. Since the gem-
dimethyl group is an inherent part of the Taxol skeleton, it was
impossible to decrease this unfavorable steric hindrance.
However, we reasoned that the increased steric hindrance of
the alkene at C13 of compounds 17a,b and 21a,b (Scheme 4)
converted into ketone 8 in 4 steps as a 3:1 mixture of E and Z
isomers.21 This ketone was then submitted to trimethylsilyl
cyanide in the presence of a catalytic amount of zinc diiodide.
The resulting cyanohydrin was reduced with DIBAL-H to the
intermediate imine, which was hydrolyzed to the racemic
aldehyde ( )-9 by exposure to silica gel. Acid 7 was also
converted into the corresponding Weinreb amide 10, and
addition of prenylmagnesium chloride to this amide furnished
ketone 11 in 95% yield as the α prenylation isomer only.
Cyanosilylation of ketone 11 followed by reduction of the
resulting cyanohydrin with DIBAL-H gave aldehyde ( )-12 in
excellent overall yield. Enantiopure aldehydes 9 and 12 could
Scheme 3. Synthesis of Metathesis Precursors 15a,b and 17a,b
B
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Organic Letters
Letter
Scheme 4. Attempts at RCDEYM and Synthesis of the ABC Tricycle of Taxol
should disfavor the undesired initial diene metathesis. This
hypothesis proved false for both the carbonate and the
benzoate compounds 17a and 21a possessing the undesired
configuration at the C1 and C2 positions as well as for the
Taxol-like benzoate 21b, which led to the carbonate 18a and
the benzoates 20a and 20b, respectively (Scheme 4).
Remarkably, reaction of the Taxol-like carbonate 17b with
Grubbs’ second-generation catalyst23 in toluene at reflux
furnished the desired tricyclic core of Taxol 22 in 45%
yield,24 along with 45% of the product of diene metathesis
18b.25
We then varied the reaction conditions in order to optimize
the yield of compound 22 (Table 1). Lowering the reaction
concentration did not change the ratio of 22 and 18b (entry 1
vs 2). Different catalysts were then evaluated. Unsurprisingly,
the Grubbs 1 catalyst26 was not active enough to perform any
metathesis reaction (entry 3). The yield of 22 increased to 59%
with the Hoveyda-Grubbs 2 complex27 (entry 4), but the best
yield (70%) was obtained with a variant of this catalyst bearing
an electron-withdrawing group on the benzylidene ligand, the
Zhan-1B catalyst28 (entry 5), along with 20% of bicycle 18b.
Changing the nature of the solvent and the reaction
temperature while using the Zhan-1B catalyst did not bring
any improvement (entries 6−9). The reaction did not proceed
in refluxing dichloromethane (40 °C), and only degradation
was observed in refluxing xylene (140 °C). Interestingly, the
reaction proceeded faster in refluxing 1,2-dichloroethane (80
°C) than in toluene at the same temperature (entry 7 vs 9).
In summary, we have constructed the ABC tricyclic core of
Taxol in 14 steps and 11% overall yield from ethyl isobutyrate.
Table 1. Optimization of the RCDEYM
a
entry
catalyst
solvent
toluene
[C] 10−3
M
yield (%) 22:18b
1
2
3
4
5
6
7
8
9
Grubbs 2
Grubbs 2
Grubbs 1
HG 2
15
3.5
5
45:45
40:40
0:0
toluene
toluene
toluene
4
59:38
70:20
0:0
Zhan-1B
Zhan-1B
Zhan-1B
Zhan-1B
Zhan-1B
toluene
3.2
3.5
3.5
3
CH2Cl2
Cl(CH2)2Cl
xylene
65:34
degradation
b
toluene, 80 °C
3
40:10
a
b
Reaction run at solvent reflux unless otherwise stated. Total yield:
50% (83% brsm).
The key step of this synthesis is an RCDEYM that leads in one
operation to the required tricycle, and we have shown that we
can direct the course of this metathesis reaction by adding an
extra methyl substituent to the olefin at C13, which does not
appear in the structure of the metathesis products. Both the
nature of the protecting group and the stereochemistry of the
diol at C1−C2 have a profound influence on the outcome of
the metathesis reaction, and only the diastereomer with the
required stereochemistry for Taxol for the C1−C2 diol,
C
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Organic Letters
Letter
(12) (a) Aldegunde, M. J.; Castedo, L.; Granja, J. R. Org. Lett. 2008,
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protected as a cyclic carbonate, undergoes the desired
RCDEYM. Calculations are in progress to rationalize these
results, and work is currently underway to achieve the formal
synthesis of Taxol.
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ASSOCIATED CONTENT
* Supporting Information
Detailed experimental procedures, compound characterization,
and crystallographic data (CIF). This material is available free
of charge via the Internet at http://pubs.acs.org.
■
S
(15) (a) Muller, B.; Delaloge, F.; den Hartog, M.; Fer
Pancrazi, A.; Prunet, J.; Lallemand, J.-Y.; Neuman, A.; Prange,
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(18) Ma, C. PhD Thesis, Ecole Polytechnique (Palaiseau, France),
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: joelle.prunet@glasgow.ac.uk.
Present Addresses
§PCAS, 23 rue Bossuet, ZI de la Vigne aux Loups 91160
Longjumeau, France.
∥Molecular Microbiology Biological Sciences School of
Environmental and Life Sciences University of Newcastle
Callaghan, NSW 2308 Australia.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(20) Bourgeois, D.; Prunet, J.; Pancrazi, A.; Prange,
Y. Eur. J. Org. Chem. 2000, 4029.
́
T.; Lallemand, J.-
Financial support for this work was provided by the CNRS, the
Ecole Polytechnique, and the University of Glasgow. We thank
Dr. Brian Millward, Honorary Research Fellow, School of
Chemistry, University of Glasgow, for a generous donation.
(21) See Supporting Information for details. Ketone 8 was also
prepared by addition of crotylmagnesium chloride to amide 10, but
could not be obtained pure due to the quality of the crotyl chloride.
(22) Grieco, P. A.; Gilman, S.; Nishizawa, M. J. Org. Chem. 1976, 41,
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(23) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999,
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(24) X-ray diffraction analysis of a derivative of 22 established the
tricyclic structure of the product and confirmed that it possesses the
required relative configuration at C1, C2, and C8 for Taxol (see
Supporting Information for details).
(25) Attempts to convert bicycle 18b to the desired tricycle 22 by
resubmitting it to the reaction conditions, with or without 2-methyl-2-
butene were unsuccessful, and only recovered 18b was obtained:
Chatterjee, A. K.; Sanders, D. P.; Grubbs, R. H. Org. Lett. 2002, 4,
1939. These results seem to indicate that the formation of compound
18b is not reversible under the reaction conditions.
(26) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H. Angew.
Chem., Int. Ed. 1995, 34, 2039.
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